Rapid Re-endothelialization Research Articles

Robust and Regular Micronano Binary Texture on the Complex Curved Surface for Enhanced Reendothelialization and Antithrombotic Performance.

Blood-contacting medical devices can easily trigger immune responses, leading to thrombosis and hyperblastosis. Constructing microtexture that provides efficient antithrombotic and rapid reendothelialization performance on complex curved surfaces remains a pressing challenge. In this work, we present a robust and regular micronano binary texture on the titanium surface, characterized by exceptional mechanical strength and precisely controlled wettability to achieve excellent hemocompatibility. Systematic in vitro and in vivo investigations confirmed that the micronano binary texture with superhydrophilic modification effectively suppressed the adhesion and activation of plasma proteins and blood cells, thereby mitigating the subsequent coagulation cascade and thrombosis. Meanwhile, the modified surface significantly upregulated the gene expression involving cell-matrix adhesion, growth factor synthesis, and calcium-mediated cytoskeleton remodeling and then accelerated the formation of a healthy and stable endothelial cell layer. This enhancement of re-endothelialization was not observed with pure titanium and superhydrophobic surfaces. Hence, superhydrophilic micronano binary texture not only significantly inhibits thrombosis but also selectively enhances the integrity and viability of the endothelial cell layer, making it a promising strategy for improving the long-term anticoagulation performance of vascular implants.

Vascular stent with immobilized anti-inflammatory chemerin 15 peptides mitigates neointimal hyperplasia and accelerates vascular healing

Endovascular stenting is a safer alternative to open surgery for use in treating cerebral arterial stenosis and significantly reduces the recurrence of ischemic stroke, but the widely used bare-metal stents (BMSs) often result in in-stent restenosis (ISR). Although evidence suggests that drug-eluting stents are superior to BMSs in the short term, their long-term performances remain unknown. Herein, we propose a potential vascular stent modified by immobilizing clickable chemerin 15 (C15) peptides on the stent surface to suppress coagulation and restenosis. Various characterization techniques and an animal model were used to evaluate the surface properties of the modified stents and their effects on endothelial injury, platelet adhesion, and inflammation. The C15-immobilized stent could prevent restenosis by minimizing endothelial injury, promoting physiological healing, restraining the platelet-leukocyte-related inflammatory response, and inhibiting vascular smooth muscle cell proliferation and migration. Furthermore, in vivo studies demonstrated that the C15-immobilized stent mitigated inflammation, suppressed neointimal hyperplasia, and accelerated endothelial restoration. The use of surface-modified, anti-inflammatory, endothelium-friendly stents may be of benefit to patients with arterial stenosis. Statement of significanceEndovascular stenting is increasingly used for cerebral arterial stenosis treatment, aiming to prevent and treat ischemic stroke. But an important accompanying complication is in-stent restenosis (ISR). Persistent inflammation has been established as a hallmark of ISR and anti-inflammation strategies in stent modification proved effective. Chemerin 15, an inflammatory resolution mediator with 15-aa peptide, was active at picomolar through cell surface receptor, no need to permeate cell membrane and involved in resolution of inflammation by inhibiting inflammatory cells adhesion, modulating macrophage polarization into protective phenotype, and reducing inflammatory factors release. The implications of this study are that C15 immobilized stent favors inflammation resolution and rapid re-endothelialization, and exhibits an inhibitory role of restenosis. As such, it helps the decreased incidence of ISR.

Nanotexture and crystal phase regulation for synergistic enhancement in re-endothelialization on medical pure titanium surface

Re-endothelialization has been recognized as a promising strategy to address the tissue hyperplasia and subsequent restenosis which are major complications associated with vascular implant/interventional titanium devices. However, the uncontrollable over-proliferation of smooth muscle cells (SMCs) limits the clinical application of numerous modified strategies. Herein, a novel modified strategy involving with a two-step anodic oxidation and annealing treatment was proposed to achieve rapid re-endothelialization function regulated by regular honeycomb nanotexture and specific anatase phase on the titanium surface. Theoretical calculation revealed that the presence of nanotexture reduced the polar component of surface energy, while the generation of anatase significantly enhanced the polar component and total surface energy. Meanwhile, the modified surface with regular nanotexture and anatase phase produced positive effect on the expression of CD31, VE-Cadherin and down-regulated α-SMA proteins expression, indicating excellent capacity of pro-endothelial regeneration and inhibition of SMCs proliferation and migration. One-month in vivo implantation in rabbit carotid arteries further confirmed that modified tube implant surface effectively accelerated confluent endothelial monolayer formation and promoted native-like endothelium tissue regeneration. By contrast, original titanium tube implant induced a disorganized tissue proliferation in the lumen with a high risk of restenosis. Collectively, this study opens us an alternative route to achieve the function that selectively promotes endothelial cells (ECs) growth and suppresses SMCs on the medical titanium surface, which has a great potential in facilitating re-endothelialization on the surface of blood-contacting titanium implant.

A Versatile Passivated Protein‐Adsorption Platform for Rapid Healing of Vascular Stents by Modulating the Microenvironment

AbstractBiodegradable stents have paved the way to treat coronary artery disease. However, rapid reendothelialization is required to solve the problems of mismatched degradation rates, localized inflammation, and insufficient biocompatibility. Herein, a novel passivated protein‐adsorption coating is synthesized by coordination chelation, oxidation, cross‐linking, polymerization, and deposition of dopamine, (‐)‐epigallocatechin gallate (EGCG), and copper ions (Cu2+) using two‐electron oxidation. This coating exhibits hierarchical functionality, that is, at the macroscale, its superhydrophilicity conveys antifouling ability; whereas at the microscale, the active groups (quinone‐, amino‐, hydroxyphenyl groups and aromatic ring) facilitate protein adsorption. Antifouling ability prevents acute thrombosis and inflammation and maintains initial microenvironment stability post‐implantation. The active groups facilitate gradual endothelial cells (ECs) adhesion. Meanwhile, the decomposition of nitric oxide (NO) donors to release NO is catalyzed by Cu2+, and EGCG alleviates or prevents oxidative stress damage, inflammatory responses, thrombosis formation, and excessive smooth muscle cells proliferation in the stent microenvironment. This provides favorable conditions for the rapid and healthy growth of ECs. This study proposes a novel strategy for rapid neointima formation comprising healthy ECs on the surfaces of biodegradable stents by depositing a passivated protein‐adsorption coating (polydopamine/EGCG/Cu), opening new possibilities for the efficient treatment of coronary artery disease.

Durable Immunomodulatory Nanofiber Niche for the Functional Remodeling of Cardiovascular Tissue.

Functional remodeling and prolonged anti-inflammatory responses are both vital for repairing damage in the cardiovascular system. Although these aspects have each been studied extensively alone, attempts to fabricate scaffolds that combine these effects have seen limited success. In this study, we synthesized salvianic acid A (SA, danshensu) blocked biodegradable polyurethane (PCHU-D) and enclosed it within electrospun nanofibers to synthesize a durable immunomodulatory nanofiber niche (DINN), which provided sustained SA release during inflammation. Given its excellent processability, mechanical properties, and shape memory function, we developed two variants of the DINN as vascular scaffolds and heart patches. Both these variants exhibited outstanding therapeutic effects in in vivo experiments. The DINN was expertly designed such that it gradually decomposes along with SA release, substantially facilitating cellular infiltration and tissue remodeling. Therefore, the DINN effectively inhibited the migration and chemotaxis of inflammatory cells, while also increasing the expression of angiogenic genes. As a result, it promoted the recovery of myocardial function after myocardial infarction and induced rapid reendothelialization following arterial orthotopic transplantation repair. These excellent characteristics indicate that the DINN holds great potential as a multifunctional agent for repairing cardiovascular tissues.

Passivation protein-adhesion platform promoting stent reendothelialization using two-electron-assisted oxidation of polyphenols

Superhydrophilic surfaces play an important role in nature. Inspired by this, scientists have designed various superhydrophilic materials that are widely used in the field of biomaterials, such as PEG molecular brushes and zwitterionic materials. However, superhydrophilic coatings with only anti-fouling properties do not satisfy the requirements for rapid reendothelialization of cardiovascular stent surfaces. Herein, a novel polyphenol superhydrophilic surface with passivated protein-adsorption properties was developed using two-electron oxidation of dopamine and polyphenols. This coating has a multiscale effects: 1) macroscopically: anti-fouling properties of superhydrophilic; 2) microscopically: protein adhesion properties of active groups (quinone-, amino-, hydroxyphenyl groups and aromatic ring). Polyphenols not only enhance the ability of coating to passivate protein-adsorption, but also make the coating have polyphenol-related biological functions. Therefore, the polyphenol and passivated protein-adsorption platform together maintain the stability of the scaffold microenvironment. This, in turn, provides favorable conditions for the growth of endothelial cells on the scaffold surface. In vivo implantation of the coated stents into the abdominal aorta resulted in uniform and dense endothelial cells covering the surface of the neointima. Moreover, new endothelial cells secreted large amounts of functional endothelial nitric oxide synthase like healthy endothelial cells. These results indicate that the polyphenol superhydrophilic coating potentially resists intra-stent restenosis and promotes surface reendothelialization. Hence, polyphenol superhydrophilic coatings with passivated protein-adsorption properties constructed by two-electron-assisted oxidation are a highly effective and versatile surface-modification strategy for implantable cardiovascular devices.

Abstract 12931: Development of Novel Targeted, Membrane-Coated Polymer Hybrid Nanoparticles for Endothelial Repair Following Balloon Angioplasty in Rat Carotid Artery Model

Background: Coronary and peripheral arterial disease remains one of the leading causes of death worldwide. Treatments include balloon angioplasty, stent placement, or bypass grafting, all of which damage the endothelium and increase the risk of thrombosis or intimal hyperplasia. Thus, there is a critical need for rapid reendothelialization following these treatments. Endothelial progenitor cell-derived (EPC) extracellular vesicles (EVs) containing proangiogenic microRNAs, such as miR126, is one of the natural mechanisms of vascular repair. However, the translational application of EVs is limited by low EV yield, functional heterogeneity, and difficult tissue targeting. Hypothesis: We hypothesize that EV-inspired hybrid nanoparticles can improve reendothelialization and modification with a specific collagen binding peptide SILY can target vascular injury. Aims: (1) Engineer and characterize a SILY modified hybrid EPC membrane coated nanoparticles (SILY-ENPs) containing a miRNA-126-loaded poly-lactic-co-glycolic acid core (miR126-PLGA) in vitro . (2) Test the therapeutic efficacy of the SILY-ENPs in an in vivo rat carotid balloon angioplasty model. Methods: EPC plasma membranes were isolated from umbilical cord blood EPCs and conjugated with SILY using copper-free Click chemistry. Membrane fragments were coextruded with miR126-PLGA to form SILY-ENPs. Particles were characterized in vitro for collagen and platelet binding and angiogenic function. In vivo function was tested in a rat carotid balloon angioplasty model. Results: SILY-ENPs were found to have increased collagen binding and decreased platelet activity. Delivery of miR126 cargo slightly improved pro-angiogenic protein expression and increased rates of reendothelialization. However, SILY-ENPs were found to stimulate hyperplasia as an adverse side-effect. Conclusions: SILY-ENPs exhibited target specificity, decreased platelet activity, and increased rates of reendothelialization, but increased intimal hyperplasia. This technology represents a novel EV inspired nanoplatform which can be tailored for treating various diseases by altering the cargo or membrane coating.

A small-diameter vascular graft immobilized peptides for capturing endothelial colony-forming cells.

Combining synthetic polymers and biomacromolecules prevents the occurrence of thrombogenicity and intimal hyperplasia in small-diameter vascular grafts (SDVGs). In the present study, an electrospinning poly (L)-lactic acid (PLLA) bilayered scaffold is developed to prevent thrombosis after implantation by promoting the capture and differentiation of endothelial colony-forming cells (ECFCs). The scaffold consists of an outer PLLA scaffold and an inner porous PLLA biomimetic membrane combined with heparin (Hep), peptide Gly-Gly-Gly-Arg-Glu-Asp-Val (GGG-REDV), and vascular endothelial growth factor (VEGF). Attenuated total reflection Fourier transform infrared (ATR-FTIR) spectroscopy, X-ray photoelectron spectroscopy (XPS), and contact angle goniometry were performed to determine successful synthesis. The tensile strength of the outer layer was obtained using the recorded stress/strain curves, and hemocompatibility was evaluated using the blood clotting test. The proliferation, function, and differentiation properties of ECFCs were measured on various surfaces. Scanning electronic microscopy (SEM) was used to observe the morphology of ECFCs on the surface. The outer layer of scaffolds exhibited a similar strain and stress performance as the human saphenous vein via the tensile experiment. The contact angle decreased continuously until it reached 56° after REDV/VEGF modification, and SEM images of platelet adhesion showed a better hemocompatibility surface after modification. The ECFCs were captured using the REDV + VEGF + surface successfully under flow conditions. The expression of mature ECs was constantly increased with the culture of ECFCs on REDV + VEGF + surfaces. SEM images showed that the ECFCs captured by the REDV + VEGF + surface formed capillary-like structures after 4weeks of culture. The SDVGs modified by REDV combined with VEGF promoted ECFC capture and rapid differentiation into ECs, forming capillary-like structures in vitro. The bilayered SDVGs could be used as vascular devices that achieved a high patency rate and rapid re-endothelialization.

Postfunctionalization of biological valve leaflets with a polyphenol network and anticoagulant recombinant humanized type III collagen for improved anticoagulation and endothelialization.

Almost all commercial bioprosthetic heart valves (BHVs) are crosslinked with glutaraldehyde (GLUT); however, issues such as immune responses, calcification, delayed endothelialization, and especially severe thrombosis threaten the service lifespan of BHVs. Surface modification is expected to impart GLUT-crosslinked BHVs with versatility to optimize service performance. Here, a postfunctionalization strategy was established for GLUT-crosslinked BHVs, which were firstly modified with metal-phenolic networks (MPNs) to shield the exposed calcification site, and then anticoagulant recombinant humanized type III collagen (rhCOLIII) was immobilized to endow them with long-term antithrombogenicity and enhanced endothelialization properties. The postfunctionalization coating exhibited promising mechanical properties and resistance to enzymatic degradation capability resembling that of GLUT-crosslinked porcine pericardium (GLUT-PP). With the introduction of meticulously tailored rhCOLIII, the anti-coagulation and re-endothelialization properties of TA/Fe-rhCOLIII were significantly improved. Furthermore, the mild inflammatory response and reduced calcification were evidenced in TA/Fe-rhCOLIII by subcutaneous implantation. In conclusion, the efficacy of the proposed strategy combining anti-inflammatory MPNs and multifunctional rhCOLIII to improve anticoagulation, reduce the inflammatory response, and ultimately achieve rapid reendothelialization was supported by both ex vivo and in vivo experiments. Altogether, the current findings may provide a simple strategy for enhancing the service function of BHVs after implantation and show great potential in clinical applications.

Combinational Growth Factor and Gas Delivery for Thrombosis Prevention.

Cardiovascular stents enable the rapid re-endothelialization of endothelial cells (ECs), and the constant suppression of smooth muscle cell (SMC) proliferation has been proved to effectively prevent thrombosis. However, the development and application of such stents are still insufficient due the delayed re-endothelialization progress, as well as the poor durability of the SMC inhibition. In this paper, we developed a mussel-inspired coating with the ability for the dual delivery of both growth factor (e.g., platelet-derived growth factor, PDGF) and therapeutic gas (e.g., nitric oxide, NO) for thrombosis prevention. We firstly synthesized the mussel-inspired co-polymer (DMHM) of dopamine methacrylamide (DMA) and hydroxyethyl methacrylate (HEMA) and then coated the DMHM on 316L SS stents combined with CuII. Afterwards, we immobilized the PDGF on the DMHM-coated stent and found that the PDGF could be released in the first 3 days to enhance the recruitment, proliferation, and migration of human umbilical vein endothelial cells (HUVECs) to promote re-endothelialization. The CuII could be "sealed" in the DMHM coating, with extended durability (2 months), with the capacity for catalyzed NO generation for up to 2 months to suppress the proliferation of SMCs. Such a stent surface modification strategy could enhance the development of the cardiovascular stents for thrombosis prevention.

Construction of functional magnetic scaffold with temperature control switch for long-distance vascular injury

Fusion of endothelial monolayer for rapid reendothelialization is the key to vascular transplantation, which is crucial for remodeling long-distance (≥10 mm) vascular injury (LDVJ) and reducing the long-term repair period. Although silk fibroin (SF) has been widely prepared as a scaffold to repair vascular injuries, it is still challenging to remodel LDVJs. The design and manufacture of functional scaffolds with a rapid reendothelialization enhancement effect are helpful to solve this problem. Here, we developed a well-designed functional magnetic scaffold (MDP) with a temperature-controlled switch, intelligently regulating the release of magnetic nanoparticles (MNPs) to induce macrophages migration and M2 polarization. The results show that the radial support force of MDP is appropriately five times higher than that of pure silk fibroin scaffold (SFC), and the degradation of MDP is delayed, which is beneficial to maintaining the integrity of the scaffold. MDP induces the migration of macrophages, upregulates the expression of repair cytokines such as TGF-β, IL-10 and VEGF, and promotes the proliferation of mouse aortic vascular smooth muscle (MOVAS) cells. More importantly, the enhanced migration of macrophages at the phase transition temperature is more conducive to the proliferation and accumulation of vascular repair-related cells, which is conducive to rapid reendothelialization. In addition, MDP also significantly regulates the polarization of macrophages to M2 type, which is conducive to the secretion of repair cytokines to further promote vascular recovery. The evaluation of endothelial cells' adhesion and function also proved that MDP could increase the expression of vascular endothelial cadherin (VE-Cad) and collagen IV (COL IV) and has the potential for rapid reendothelialization. The replacement model in vivo animal experiments further proved that MDP exhibited a better repair effect than SFC, providing a new option for the repair of LDVJ in the future.

Coupled benefits of nanotopography and titania surface chemistry in fostering endothelialization and reducing in-stent restenosis in coronary stents

Recent advances in coronary stents have all been distinctively focused towards directing re-endothelialization with minimal in-stent restenosis, potentially via alterations in surface topographical cues, for augmenting the efficacy of vascular implants. This perspective was proven by our group utilizing a simple and easily scalable nanosurface modification strategy on metallic stents devoid of any drugs or polymers. In the present work, we explore the impact of surface characteristics in modulating this cell response in-vitro and in-vivo, using titania coated cobalt-chromium (CC) stents, with and without nanotopography, in comparison to commercial controls. Interestingly, titania nanotopography facilitated a preferential cell response in-vitro as against the titania coated and bare CC surfaces, which can be attributed to surface topography, hydrophilicity, and roughness. This in turn altered the cellular adhesion, proliferation and focal contact formations of endothelial and smooth muscle cells. We also demonstrate that titania nanotexturing plays a pivotal role in fostering rapid re-endothelialization with minimal neointimal hyperplasia, leading to excellent in-vivo patency of CC stents post 8 weeks implantation in rabbit iliac arteries, in comparison to bare CC, nano-less titania coated CC, and commercial drug-eluting stents (CC DES), without administering antiplatelet agents. This exciting result for the drug and polymer-free titania nanotextured stents, in the absence of platelet therapy, reveals the possibility of proposing an alternative to clinical DES for coronary stenting.

Review of Polymeric Biomimetic Small-Diameter Vascular Grafts to Tackle Intimal Hyperplasia.

Small-diameter artificial vascular grafts (SDAVG) are used to bypass blood flow in arterial occlusive diseases such as coronary heart or peripheral arterial disease. However, SDAVGs are plagued by restenosis after a short while due to thrombosis and the thickening of the neointimal wall known as intimal hyperplasia (IH). The specific causes of IH have not yet been deduced; however, thrombosis formation due to bioincompatibility as well as a mismatch between the biomechanical properties of the SDAVG and the native artery has been attributed to its initiation. The main challenges that have been faced in fabricating SDAVGs are facilitating rapid re-endothelialization of the luminal surface of the SDAVG and replicating the complex viscoelastic behavior of the arteries. Recent strategies to combat IH formation have been mostly based on imitating the natural structure and function of the native artery (biomimicry). Thus, most recently, developed grafts contain a multilayered structure with a designated function for each layer. This paper reviews the current polymeric, biomimetic SDAVGs in preventing the formation of IH. The materials used in fabrication, challenges, and strategies employed to tackle IH are summarized and discussed, and we focus on the multilayered structure of current SDAVGs. Additionally, the future aspects in this area are pointed out for researchers to consider in their endeavor.

Egg Shell Membrane as an Alternative Vascular Patch for Arterial Angioplasty.

Introduction: The egg shell membrane (ESM) is always considered as waste, but recent studies have shown that it has the potential to yield rapid re-endothelialization in vitro. We hypothesized that ESM and heparin-conjugated ESM (HESM) can be used as arterial patch in a rat aortic angioplasty model. Method: Sprague-Dawley rat (200 g) abdominal aortic patch angioplasty model was used. Decellularized rat thoracic aorta (TA) patch was used as the control; ESM patch was made of raw chicken egg; heparin-coated ESM (HESM) patch was made by using dopamine; anticoagulation properties were verified using platelet adhesion tests; the TA, ESM, and HESM patches were implanted to the rat aorta and harvested at day 14; and the samples were examined by immunohistochemistry and immunofluorescence. Result: The ESM patch showed a similar healing process to the TA patch; the cells could migrate and infiltrate into both patches; there was a neointima with von Willebrand factor-positive endothelial cells; the endothelial cells acquired arterial identity with Ephrin-B2- and dll-4-positive cells; there were proliferating cell nuclear antigen (PCNA)-positive cells, and PCNA and alpha smooth muscle actin dual-positive cells in the neointima in both groups. Heparin was conjugated to the patch successfully and showed a strong anticoagulation property in vitro. HESM could decrease mural thrombus formation after rat aortic patch angioplasty. Conclusion: The ESM is a natural scaffold that can be used as a vascular patch; it showed a similar healing process to decellularized TA patch; HESM showed anticoagulation property both in vitro and in vivo; and the ESM may be a promising vascular graft in the clinic.

Bovine serum albumin-based biomimetic gene complexes with specificity facilitate rapid re-endothelialization for anti-restenosis

Re-endothelialization is a critical problem to inhibit postoperative restenosis, and gene delivery exhibits great potential in rapid endothelialization. Unfortunately, the therapeutic effect is enormously limited by inefficient specificity, poor biocompatibility and in vivo stability owing largely to the complicated in vivo environment. Herein, we developed a series of platelet membrane (PM) cloaked gene complexes based on natural bovine serum albumin (BSA) and polyethyleneimine (PEI). The gene complexes aimed to accelerate re-endothelialization for anti-restenosis via pcDNA3.1-VEGF165 (VEGF) plasmid delivery. Based on BSA and PM coating, these gene complexes exhibited good biocompatibility, stability with serum and robust homing to endothelium-injured site inherited from platelets. Besides, they enhanced the expression of VEGF protein by their high internalization and nucleus accumulation efficiency, and also substantially promoted migration and proliferation of vascular endothelial cells. The biological properties were further optimized via altering PEI and PM content. Finally, rapid recovery of endothelium in a carotid artery injured mouse model (79% re-endothelialization compared with model group) was achieved through two weeks’ treatment by the PM cloaked gene complexes. High level of expressed VEGF in vivo was also realized by the gene complexes. Moreover, neointimal hyperplasia (IH) was significantly inhibited by the gene complexes according to in vivo study. The results verified the great potential of the PM cloaked gene complexes in re-endothelialization for anti-restenosis. Statement of significanceRapid re-endothelialization is a major challenge to inhibit postoperative restenosis. Herein, a series of biodegradable and biocompatible platelet membrane (PM) cloaked gene complexes were designed to accelerate re-endothelialization for anti-restenosis via pcDNA3.1-VEGF165 (VEGF) plasmid delivery. The PM cloaked gene complexes provided high VEGF expression in vascular endothelial cells (VECs), rapid migration and proliferation of VECs and robust homing to endothelium-injured site. In a carotid artery injured mouse model, PM cloaked gene complexes significantly promoted VEGF expression in vivo, accelerated re-endothelialization and inhibited neointimal hyperplasia due to their good biocompatibility and superior specificity. Overall, the optimized PM cloaked gene complexes overcomes multiple obstacles in gene delivery for re-endothelialization and can be a promising candidate for gene delivery and therapy of postoperative restenosis.

GDF11 alleviates neointimal hyperplasia in a rat model of artery injury by regulating endothelial NLRP3 inflammasome activation and rapid re-endothelialization

BackgroundNeointimal hyperplasia induced by interventional surgery can lead to progressive obliteration of the vascular lumen, which has become a major factor affecting prognosis. The rate of re-endothelialization is known to be inversely related to neointima formation. Growth differentiation factor 11 (GDF11) is a secreted protein with anti-inflammatory, antioxidant, and antiaging properties. Recent reports have indicated that GDF11 can improve vascular remodeling by maintaining the differentiated phenotypes of vascular smooth muscle cells. However, it is not known whether and how GDF11 promotes re-endothelialization in vascular injury. The present study was performed to clarify the influence of GDF11 on re-endothelialization after vascular injury.MethodsAn adult Sprague–Dawley rat model of common carotid artery balloon dilatation injury was surgically established. A recombinant adenovirus carrying GDF11 was delivered into the common carotid artery to overexpress GDF11. Vascular re-endothelialization and neointima formation were assessed in harvested carotid arteries through histomolecular analysis. CCK-8 analysis, LDH release and Western blotting were performed to investigate the effects of GDF11 on endothelial NLRP3 inflammasome activation and relevant signaling pathways in vitro.ResultsGDF11 significantly enhanced re-endothelialization and reduced neointima formation in rats with balloon-dilatation injury by suppressing the activation of the NLRP3 inflammasome. Administration of an endoplasmic reticulum stress (ER stress) inhibitor, 4PBA, attenuated endothelial NLRP3 inflammasome activation induced by lysophosphatidylcholine. In addition, upregulation of LOX-1 expression involved elevated ER stress and could result in endothelial NLRP3 inflammasome activation. Moreover, GDF11 significantly inhibited NLRP3 inflammasome-mediated endothelial cell pyroptosis by negatively regulating LOX-1-dependent ER stress.ConclusionsWe conclude that GDF11 improves re-endothelialization and can attenuate vascular remodeling by reducing endothelial NLRP3 inflammasome activation. These findings shed light on new treatment strategies to promote re-endothelialization based on GDF11 as a future target.

Comparison of Surface Functionalization of PLGA Composite to Immobilize Extracellular Vesicles

Endothelialization by materials provides a promising approach for the rapid re-endothelialization of a cardiovascular implantation. Although previous studies have focused on improving endothelialization through the immobilization of bioactive molecules onto the surface of biodegradable implants, comparative studies of effective surface modification have not yet been reported. Here, we conducted a comparative study on the surface modification of poly(lactide-co-glycolide) (PLGA)-based composites to graft mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) using three different materials, fibronectin (FN), polyethylenimine (PEI), and polydopamine (PDA), which have different bond strengths of ligand–receptor interaction, ionic bond, and covalent bond, respectively. Further in vitro analysis exhibited that MSC-EVs released from all modified films sustainably, but the MSC-EVs grafted onto the surface coated with PEI are more effective than other groups in increasing angiogenesis and reducing the inflammatory responses in endothelial cells. Therefore, the overall results demonstrated that PEI is a desirable coating reagent for the immobilization of MSC-EVs on the surface of biodegradable implants.

Dichloroacetate inhibits the degeneration of decellularized cardiovascular implants.

OBJECTIVESIntima hyperplasia is a major issue of biological cardiovascular grafts resulting in progressive in vivo degeneration that particularly decreases the durability of coronary and peripheral vascular bypasses. Previously, dichloroacetate (DCA) has been reported to prevent the formation of hyperplastic intima in injured arteries. In this study, the effect of DCA on the neointima formation and degeneration of decellularized small-caliber implants was investigated in a rat model.METHODSDonor rat aortic grafts (n = 22) were decellularized by a detergent-based technique, surface-coated with fibronectin (50 µl ml−1, 24 h incubation) and implanted via anastomoses to the infrarenal aorta of the recipients. Rats in the DCA group (n = 12) received DCA via drinking water during the whole follow-up period (0.75 g l−1), while rats without DCA treatment served as controls (n = 10). At 2 (n = 6 + 5) and 8 (n = 6 + 5) weeks, the grafts were explanted and examined by histology and immunofluorescence.RESULTSSystemic DCA treatment inhibited neointima hyperplasia, resulting in a significantly reduced intima-to-media ratio (median 0.78 [interquartile range, 0.51–1.27] vs 1.49 [0.67–2.39] without DCA, P < 0.001). At 8 weeks, neointima calcification, as assessed by an established von Kossa staining-based score, was significantly decreased in the DCA group (0 [0–0.25] vs 0.63 [0.06–1.44] without DCA, P < 0.001). At 8 weeks, explanted grafts in both groups were luminally completely covered by an endothelial cell layer. In both groups, inflammatory cell markers (CD3, CD68) proved negative.CONCLUSIONSSystemic DCA treatment reduces adverse neointima hyperplasia in decellularized small-caliber arterial grafts, while allowing for rapid re-endothelialization. Furthermore, DCA inhibits calcification of the implants.

Phenolic-amine chemistry mediated synergistic modification with polyphenols and thrombin inhibitor for combating the thrombosis and inflammation of cardiovascular stents

Antithrombogenicity, anti-inflammation, and rapid re-endothelialization are central requirements for the long-term success of cardiovascular stents. In this work, a plant-inspired phenolic-amine chemistry strategy was developed to combine the biological functions of a plant polyphenol, tannic acid (TA), and the thrombin inhibitor bivalirudin (BVLD) for tailoring the desired multiple surface functionalities of cardiovascular stents. To realize the synergistic modification of TA and BVLD on a stent surface, an amine-bearing coating of plasma polymerized allylamine was firstly prepared on the stent surface, followed by the sequential conjugation of TA and BVLD in alkaline solution based on phenolic-amine chemistry (i.e., Michael addition reaction). TA and BVLD were successfully immobilized onto the stent surface with considerable amounts of 330 ± 12 and 930 ± 80 ng/cm2, respectively. The abundant phenolic hydroxyl groups of TA imparted the stent with ability to suppress inflammation. Meanwhile, BVLD provided an antithrombogenic and endothelial-friendly microenvironment. As a result, the combined functions of the TA and BVLD facilitate the rapid stent re-endothelialization for reduced intimal hyperplasia in vivo, and may be a promising strategy to address the clinical complications associated with restenosis and late stent thrombosis.

A coaxially structured trilayered gallic acid-based antioxidant vascular graft for treating coronary artery disease

Atherosclerosis is the most common type of cardiovascular disease that involves blockage of the coronary arteries of the heart. The current surgical procedure followed in clinical settings to treat abnormal narrowing of blood vessels is the percutaneous coronary intervention. This technique involves a mesh-like, tubular construct called a stent, which is surgically placed inside arteries to treat narrowed vessels and avoid blockage. However, most of the implants suffer from restenosis problem, due to proliferation and migration of vascular smooth muscle cells (SMCs) within the stents. In this work, a biomimetically designed trilayered electrospun conduit of poly-glycolic acid and polycaprolactone blend was sandwiched between gallic acid-containing antioxidant oxygen-releasing polyurethane to serve as a potential stent to avoid restenosis. The selectivity of gallic acid towards inhibiting the growth of SMCs will enable rapid re-endothelialization of the damaged blood vessels. The scaffolds were fabricated by electrospinning of the polymers on a 2 mm diameter rotating collector to mimic the vessel diameter of the coronary arteries. Characterization of the scaffolds has been carried out using fourier transform infrared spectroscopy, electron microscopy, thermal analysis, antioxidant potential assay, and haemocompatibility. The tubular constructs had a strut thickness of ~ 275 µm and could scavenge 92% of the free radicals in just 15 min. The fabricated material was also able to attenuate induced oxidative stress on cells and maintained 68% cell viability. More importantly, the presence of gallic acid was able to reduce the growth of smooth muscle cells by 40% on the scaffolds, making it a feasible material for stent fabrication. The fabricated polymer-based material will be a potent cardiovascular implant for treating blocked arteries.